Monday, March 16, 2020

Coronavirus vs the human immune system: the brutal microscopic war for survival

15 March, 2020

HONG KONG — When a virus enters the human body, it's in a race against time to hijack cells, reproduce and spread. Its survival depends on it, because once the body's immune system detects the intruder an all-out microscopic war follows.

While the Sars-CoV-2 virus behind the present pandemic has killed thousands and spread fear around the world, the immune system — which has evolved over millions of years of fighting pathogens — shows no such trepidation. It responds with ferocity to obliterate the invader, led by armies of killer T-cells.

That immune system is one reason the human species still exists, but in some cases its fight against viruses can resemble the scorched-earth policy of warfare, where everything in the area of the conflict takes damage, meaning body tissue itself. The immune system takes no prisoners.

But before the war at the cellular level, the virus slips into the body, navigating past defences in the mucus that gathers in noses and throats, on the hunt for cells it can commandeer. At the same time, it's trying to disguise its presence to avoid tripping the chemical alarm system of the immune system — a deadly game of hide-and-seek.

In the first few hours after the pathogen's entry, it was "almost like a dance between the innate immune response and the virus", said Mr Gene Olinger, an immunologist with the US-based scientific institute MRIGlobal. The virus tries different tricks to dodge the immune system's many detection devices.

This was the start of what become an "arms race" between the virus and immune system, said Ms Marjolein Kikkert, an associate professor who researches this type of biochemical conflict at Leiden University Medical Centre in the Netherlands.

"All viruses, including this one, will have multiple ways that they look to circumvent or suppress immune response ... there's an arms race, especially in the beginning, when the virus is trying to prevent these first responses," Ms Kikkert said.

Once the immune system is triggered and a T-cell finds a body cell that has become a virus factory, it typically latches on and fires molecules that punch through the cell's membrane, killing it and everything inside.

But as Sars-CoV-2 is a newly discovered virus, researchers have not had enough laboratory time to determine the specifics of how the battle plays out. That leaves questions like why some healthy people infected with Sars-CoV-2 become severely ill and others do not, researchers have said.

Much of what is suspected about how the body fights back is based on research on the body's immune response to closely related coronavirus infections, such as Middle East respiratory syndrome (Mers) and severe acute respiratory syndrome (Sars). There are also the clinical records of patients with Covid-19, the disease caused by Sars-CoV-2.

What that indicates is that "every part of the immune system is needed to clear this virus", according to Mr Stanley Perlman, a professor of immunology at the University of Iowa, whose lab is now replenishing its stock of lab mice genetically engineered for research on immune response to Sars.

As the body's immune response can be so aggressive, researchers say that the war against the virus can do damage that causes fatal repercussions in the body.

In particular, Sars-CoV-2 attacks the lungs, an especially sensitive battleground. Also, as the immune system tries to fight a virus that it has never before encountered, it can go into overdrive, causing excessive damage to adjoining cells and tissue.

The body's early-warning system for invading pathogens was multilayered, Ms Kikkert said. An abnormality inside a cell would typically trigger a "cascade" of cell signals.

She said this led to the production of "alarm bell" proteins that warned surrounding cells about the presence of the virus and triggered a flood of immune molecules, creating an "antiviral state".

As more alarms sound throughout the body, the Sars-CoV-2 virus races to propagate and attack more cells. When T-cells arrive to hunt, capture and kill infected cells, the lungs become a battleground, swelling with immune cells, molecules and the fluid that they use to navigate.

Mr Olinger said that once a T-cell found an infected cell it latched on, "almost like a Velcro connection". "These cells will attach and send molecules that go through that cell and start to kill it," he said.

Meanwhile, antibodies, Y-shaped proteins, also arrive and swarm onto the virus, smothering the spikes it uses to attach to healthy cells. Larger white blood cells called macrophages also sweep in, swallowing big clusters of dead virus particles.

As this cellular carnage spreads, dead cells pile up in the lungs.

"They are clogging the airways and reducing the oxygen flow," said Ms Ashley St John, an assistant professor at Duke-NUS Medical School in Singapore who researches immune pathology.

"You need that tissue to be able to stretch and fill with oxygen, but at the same time you are filling it with immune cells and fluid ... it can prevent someone who is trying to breathe from getting enough oxygen," she said.

Some patients who recover from this stage, their lungs can heal. Others may recover, but suffer lasting damage.

China released data at the end of February that indicates that about 80 per cent of the Sars-CoV-2 infections were mild to moderate, while 14 per cent were severe. The remaining 6 per cent of critical patients may have suffered respiratory failure, septic shock, and multiple organ failure.

Globally, about 3.4 per cent of infected people might die from a Sars-CoV-2 infection, the World Health Organization (WHO) said last week, although that number may change as disease controls evolve. In China, the fatality rate fell during the course of the outbreak and the increase in infections.

In interviews, researchers said that the exact way Sars-CoV-2 behaved in the body was still being investigated, but it was clear it took the heaviest toll on the elderly and people with weakened immune systems.

More than 20 per cent of infected people aged over 80 were likely to die. Death rates for those with cardiovascular disease, diabetes, and chronic respiratory disease are double the average rate, according to statistics from the WHO-China Joint Mission on Covid-19 published at the end of February.

Some researchers suspect that in the "hide-and-seek" period, Sars-CoV-2 compromises the early immune response, either by dividing too rapidly for the system to keep up or disrupting the way the immune system regulates itself.

There was some evidence this can push a panicked system into overdrive and a "cytokine storm" follows that causes tissue inflammation.

"With a cytokine storm you have a situation where the brakes aren't working and you have all of these [immune] products [going] out of control ... cells infiltrating into the tissue, breakdown of blood vessels," St John said.

As the body sent out alarms for cells to come to fight the virus, too many or the wrong combination could show up, causing excessive tissue damage, Mr Olinger said.

"The lung is the worst place to have that happen. Those cells are there to kill, they are there to encapsulate, and control the infection ... over-response can lead to the damage in the lungs. Cells in that region are not able to transfer oxygen ... it can lead to death of the tissue."

An overwhelming immune response could also lead to death itself, researchers said.

[Over-reaction is as bad as under-reaction. Those panicky humans who want to close the borders, close the schools, stop the planes, don't let the cruise ship dock, buy up all the toilet paper are all responding from fear and panic and over-reacting.]

Getting to the bottom of the "dance" between the virus and the immune system's response was something that was hard to do without watching it play out in cells and in animals, Mr Olinger said.

"The reality is that until you have the virus in hand you really can't answer a lot of those questions," he added.

"[This virus] turned science upside down on us, because we know more about the genomic sequence now, whereas in the past other outbreaks that would come way after we had grown the virus and played with it in the laboratory, known how it performs in different cell types."

That is the work now facing researchers like those in Mr Perlman's laboratory as they hope to use mice to get a ringside seat to the fight between Sars-CoV-2 and a mammal immune system.

Such work needed to be done to work out how to build a Sars-CoV-2 vaccine, Mr Perlman said.

"How do you make a vaccine that works well if you are not sure what you need to protect a person from infection?"


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